Sjgren syndrome (SS) is a common autoimmune disease affecting millions of patients in the US that targets oral and ocular mucosa and their secretory glands. SS causes the most severe aqueous deficient dry eye disease that often results in disabling eye irritation and photophobia. There is mounting evidence that the microbiome, the community of microorganisms that inhabit the body, has a potent immunoregulatory functions. In this proposal we seek to elucidate the relationship between SS and the intestinal microbiota with the eventual goal of identifying therapeutic targets within the eye and/or the microbiota with which to treat SS. Evidence suggests that intestinal dysbiosis (microbial imbalance) contributes to the pathogenesis of SS. We hypothesize that intestinal microbiota support maintenance of the homeostatic mucosal immune environment and suppress desiccation-induced inflammation on the ocular surface. Reconstitution of normal commensal microbiota would promote restoration of ocular mucosal homeostasis. To test our hypothesis, we propose three Specific Aims: Specific Aim 1 will test the hypothesis that among patients presenting with eye irritation, those with SS have commensal fecal dysbiosis resulting in decreased levels of the anti-inflammatory short chain fatty acid (SCFA) butyrate in the stool compared to patients with other types of tear dysfunction and normal control subjects. In Specific Aim 2 we will test hypothesis that intestinal dysbiosis modulates the inflammatory response to stress at distant mucosal sites, specifically ocular inflammation, in acute and chronic murine models of SS. Specific Aim 3 will test the hypothesis that commensal intestinal microbiota maintains conjunctival goblet cell density and prevents desiccation-induced goblet loss by generating Tregs and producing SCFA butyrate. Results of this proposal will have potential to demonstrate a novel new paradigm for maintenance of homeostasis in mucosal tissues throughout the body, including the ocular surface that has a very low abundance microbiota, by commensal intestinal microbiota and their metabolites such as butyrate. Furthermore, they will provide rationale for a novel treatment approach utilizing commensal fecal microbiota to enhance natural immunoregulatory mechanisms to suppress development of mucosal autoimmune disease.